Previous investigations from our laboratory revealed that Notch is expressed by osteoblasts and its synthesis is regulated by glucocorticoids. Notch plays a critical role in osteoblastogenesis and its deletion results in serious developmental defects and neonatal lethality. Its over expression in the skeleton causes osteopenia secondary to an inhibitory effect on osteoblastogenesis. Although the activation of the canonical Notch signaling pathway induces the expression of hairy enhancer of split (HES)-1, HES-1 over expression does not recapitulate all the effects of Notch, and alternate signals, such as HEY-1 also play a role in the inhibitory effects of Notch in cells of the osteoblastic lineage. Central to the inhibitory actions of Notch is the suppression of the Wnt/?-catenin signaling pathway.
The aim of the proposed studies is to understand the function of Notch and HES-1 in bone in vivo and in vitro and define mechanisms involved. For this purpose, we will use transgenic mouse lines over expressing Notch or HES-1 in the bone environment, and mice carrying conditional deletions of notch1 and 2 or hes-1.
Our specific aims are: 1) To explore the mechanism of action of Notch in cells of the osteoblastic lineage, particularly mechanisms involved in its inhibitory effects on Wnt/?- catenin;2) To determine the function of HES-1 in vivo by transgenic over expression of HES-1 under the control of the type I collagen promoter, and by targeted hes-1 conditional deletion. The skeletal phenotype of mice misexpressing HES-1 will be compared to that of wild type mice and determined by histomorphometry, contact radiography, densitometry and micro CT scanning;and 3) To determine the mechanism of action of HES-1 in vitro and signals responsible for its effects on osteoblastogenesis. The impact of Notch and HES-1 on bone remodeling and mechanisms involved will be determined. These investigations should clarify the role of Notch and HES-1 in bone cell function.

Public Health Relevance

This project will provide novel information on intracellular proteins that regulate the function of bone forming cells, and is relevant to our understanding of mechanisms involved in osteoporosis and developments of new therapies for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045227-19
Application #
8288800
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Malozowski, Saul N
Project Start
1991-09-30
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
19
Fiscal Year
2012
Total Cost
$294,391
Indirect Cost
$81,219
Name
St. Francis Hospital and Medical Center
Department
Type
DUNS #
077314656
City
Hartford
State
CT
Country
United States
Zip Code
06105
Adami, Giovanni; Rossini, Maurizio; Gatti, Davide et al. (2016) Hajdu Cheney Syndrome; report of a novel NOTCH2 mutation and treatment with denosumab. Bone 92:150-156
Canalis, Ernesto; Zanotti, Stefano (2016) Hajdu-Cheney Syndrome, a Disease Associated with NOTCH2 Mutations. Curr Osteoporos Rep 14:126-31
Canalis, Ernesto; Schilling, Lauren; Yee, Siu-Pok et al. (2016) Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption. J Biol Chem 291:1538-51
Choudhary, Shilpa; Canalis, Ernesto; Estus, Thomas et al. (2015) Cyclooxygenase-2 suppresses the anabolic response to PTH infusion in mice. PLoS One 10:e0120164
Mirza, Faryal; Canalis, Ernesto (2015) Management of endocrine disease: Secondary osteoporosis: pathophysiology and management. Eur J Endocrinol 173:R131-51
DeMambro, Victoria E; Le, Phuong T; Guntur, Anyonya R et al. (2015) Igfbp2 Deletion in Ovariectomized Mice Enhances Energy Expenditure but Accelerates Bone Loss. Endocrinology 156:4129-40
Canalis, Ernesto; Kranz, Lauren; Zanotti, Stefano (2014) Nemo-like kinase regulates postnatal skeletal homeostasis. J Cell Physiol 229:1736-43
Canalis, Ernesto; Zanotti, Stefano (2014) Hajdu-Cheney syndrome: a review. Orphanet J Rare Dis 9:200
Canalis, Ernesto; Zanotti, Stefano; Smerdel-Ramoya, Anna (2014) Connective tissue growth factor is a target of notch signaling in cells of the osteoblastic lineage. Bone 64:273-80
Zanotti, Stefano; Kalajzic, Ivo; Aguila, Hector Leonardo et al. (2014) Sex and genetic factors determine osteoblastic differentiation potential of murine bone marrow stromal cells. PLoS One 9:e86757

Showing the most recent 10 out of 89 publications